Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca sensitizer. Our findings suggest that both methods of increasing myofilament Ca sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (k); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I/I ratio from X-ray diffraction. Computational modeling suggests that Ca sensitization through this cTnC mutation or bepridil accelerates k primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in k, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.

Hypothesis Flexible electrode interaction with intracochlear structures in a noise-damaged region of the cochlea can lead to measureable electrophysiologic changes. Background An emerging goal in cochlear implantation is preservation of residual hearing subsequently allowing for combined electric and acoustic stimulation (EAS). However, residual hearing is at least partially lost in most patients as a result of electrode insertion. A gerbil model was used to examine changes to acoustically evoked cochlear potentials during simulated cochlear implantation. Methods Gerbils were partially deafened by noise exposure to mimic residual hearing in human cochlear implant candidates. After one month, round window (RW) and intracochlear recordings during flexible electrode insertion were made in response to 1 kHz tone burst stimuli at 80 dB SPL. After the insertion the cochleas were histologically examined for hair cell loss due to the noise exposure and trauma due to the electrode insertion. Results Anatomical damage from the flexible electrode was not observable in most cases. However, insertions caused response declines that were on average greater than the controls, although some losses were similar to the controls. The CM was more sensitive than the CAP for detecting cochlear disturbance. Conclusions Because response reductions occurred in the absence of anatomical damage, disturbances in the fluid at the base appear to affect responses from the apex. The losses were less than in previous experiments where the basilar membrane was penetrated.

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Background Detecting delirium with standardized assessment tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is important, but such detection is frequently hampered by poor documentation and inappropriate “unable to assess” responses (in noncomatose patients). Objective To identify patient, clinical, and workplace factors that may impede or facilitate appropriate delirium assessment through use of the CAM-ICU, specifically documentation and inappropriate “unable to assess” responses. Methods An electronic health record–based data set was used to quantify CAM-ICU documentation and inappropriate “unable to assess” responses during 24 months. Associated patient (eg, age), clinical (eg, diagnosis), and workplace (eg, geographic location within the ICU, shift) factors were evaluated with multivariable regression. Results Of 28 586 CAM-ICU documentation opportunities, 66% were documented; 16% of documentations in alert or lightly sedated patients had inappropriate “unable to assess” responses. Night shift was associated with lower CAM-ICU documentation rates (P = .001), whereas physical restraints and location on side B (rather than side A) of the ICU were associated with higher documentation rates (P < .05 for both). Age older than 80 years, non-White race, intubation, and physical restraints were associated with more inappropriate “unable to assess” responses (all P < .05), as was infusion of propofol, midazolam, dexmedetomidine, or fentanyl (all P < .05). Conclusion Data from electronic health records can identify patient, clinical, and workplace factors associated with CAM-ICU documentation and inappropriate “unable to assess” responses, which can help target quality improvement efforts related to delirium assessment.